PROJECT SUMMARY Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the chronic presence of both motor and vocal tics. Recent epidemiologic studies show over 100,000 school children are affected by this syndrome, often with associated behavioral comorbidities that interfere with scholastic performance and social development. While primarily a disease of childhood that improves with age, a subset of patients are refractory to medication and continue to be afflicted into adulthood. Deep brain stimulation (DBS) has emerged as a treatment option for these severely affected patients and while many targets for DBS therapy have been identified, the primary target is the centromedian-parafascicular complex (CMPf) of the thalamus. The largest Tourette?s DBS clinical trial to date targeting the CMPf found a 52% reduction in the Yale Global Tic Severity Scale, a promising result that shows its potential. Despite this clinical benefit, the neurobiological mechanism by which DBS of the CMPf alleviates symptoms of TS is not understood. Previous studies have implicated increased extracellular dopamine levels in the striatum with the pathophysiology of this disease and our preliminary results using fast scan cyclic voltammetry (FSCV) during CMPf DBS suggest the CMPf can modulate these levels. These findings indicate that DBS of the CMPf may alter extracellular striatal dopamine levels and this may be correlated with reduced tic behavior. To test this, we seek to elucidate if CMPf stimulation leads to a dopaminergic response in the dorsal striatum. We will employ optogenetic and electrical stimulation to do so and record extracellular levels of phasic and tonic changes in dopamine with FSCV and multiple cyclic square wave voltammetry, respectively. A rat model of TS will be employed to characterize the effects of CMPF DBS on extracellular striatal dopamine levels and tic behavior. Pharmacological manipulations will be applied to mechanistically assess if CMPf stimulation-evoked changes in dopamine release are required for amelioration of TS-related tic behavior.